Neurological disorders and injuries frequently result in spasticity and involuntary muscle contractions that interfere with speech, movement and activities of daily living. Current approaches to reduce spasticity, such as selective dorsal rhizotomy, oral medications, or injections of botulinum toxin, have important limitations. There is currently no treatment for spasticity that provides targeted, tunable and rapidly reversible inhibition of unwanted muscle activity. This proposal describes a novel strategy to achieve precise, tunable, and reversible inhibition of motor neuron and muscle activity in vivo. Our approach is made possible by the recent discovery of optogenetics, a technique that enables the use of light-sensitive ion channels to facilitate optical excitation or inhibition of mammalian neurons. Our laboratory has recently reported the first use of optogenetics to excite sciatic nerve motor neurons in transgenic mice. However, it is unknown if a similar approach can be used to inhibit motor neuron activity using halorhodopsin (NpHR), a light sensitive ion channel that hyperpolarizes axons in response to light and impedes action potential propagation along a nerve. Our first aim is to apply light to the sciatic nerve of transgenic mice that express NpHR in their motor neuron axons. We will ask whether the application of light can block action potentials induced by electric nerve stimulation in a tunable and reversible manner and thereby prevent muscle contraction. Our preliminary results in anesthetized animals indicate that such inhibition is not only possible, but is repeatable and robust. After we characterize the light delivery properties required for effective inhibition, we will build an implantable light delivery device an use it to achieve motor neuron inhibition in freely moving transgenic mice. Finally, as a necessary prelude to future clinical use of this technology, we will translate this work to non-transgenic animals. For this purpose we will use state of the art gene therapy techniques to selectively deliver the NpHR gene to targeted motor neuron pools in a manner that is readily translated to humans. This project will lay the foundation for optogenetic modulation of activity i motor neurons and other peripheral nerves. Successful demonstration of optical inhibition will provide a proof-of-principle for a novel treatment for spasticity. Various components of this project, including techniques for opsin delivery to target nerves and the development of an implantable light delivery device, are needed to enable optogenetics-based treatments for a variety of other disorders. PUBLIC HEALTH RELEVANCE: Neurological disorders and injuries, such as cerebral palsy, stroke, and spinal cord injury frequently result in spasticity that interferes with activities of dily living. Current treatments for spasticity, such as ablative surgery or injections of neurotoxins, have important limitations. Here we propose to develop a powerful new technology that enables precise control of unwanted motor neuron and muscle activity that is typical in spasticity. This technology has the potential to improve the treatment of spasticity and other diseases in which precise control of peripheral neural activity is needed.